Clinical Studies Experience

Because clinical trials are conducted under widely
varying conditions, adverse reaction rates observed in the clinical trials of a
drug cannot be directly compared to rates in the clinical trials of another
drug and may not reflect the rates observed in practice.

STAXYN: Safety of STAXYN was evaluated in
two identical multi-national, randomized, double-blind, placebo-controlled
trials. In both pivotal studies, enrollment was stratified so that
approximately 50% of patients were ≥ 65 years old. Approximately 8% (n=29)
were ≥ 75 years old. An integrated analysis of both studies included a
total of 355 subjects that received STAXYN compared to 340 subjects that
received placebo (mean age was 61.7, range 21.0 to 88.0; 68% White, 5% Black,
6% Asian, 11% Hispanic and 11% Other). The discontinuation rates due to adverse
reactions were 1.4% for STAXYN compared to 0.6% for placebo. Table 1 below
details the most frequently reported adverse reactions.

Table 1: Adverse drug reactions reported by ≥ 2%
of the patients treated with STAXYN and more frequent on drug than placebo in
controlled trials

All Vardenafil Studies

Vardenafil film-coated
tablets and STAXYN has been administered to over 17,000 men (mean age 54.5,
range 18–89 years; 70% White, 5% Black, 13% Asian, 4% Hispanic and 8% Other)
during controlled and uncontrolled clinical trials worldwide. The number of patients
treated for 6 months or longer was 3357, and 1350 patients were treated for at
least 1 year.

In the placebo-controlled
clinical trials for vardenafil film-coated tablets and STAXYN, the
discontinuation rate due to adverse events was 1.9% for vardenafil compared to
0.8% for placebo.

The following section
identifies additional, less frequent adverse reactions ( < 2%) reported during
the clinical development of vardenafil film-coated tablets and STAXYN. Excluded
from this list are those adverse reactions that are infrequent and minor, those
events that may be commonly observed in the absence of drug therapy, and those
events that are not reasonably associated with the drug:

Postmarketing Experience

The following adverse reactions
have been identified during post approval use of vardenafil in the film-coated
tablet formulation. Because these reactions are reported voluntarily from a
population of uncertain size, it is not always possible to estimate their
frequency or establish a causal relationship to drug exposure.

Ophthalmologic: Non-arteritic anterior
ischemic optic neuropathy (NAION), a cause of decreased vision including permanent
loss of vision, has been reported rarely postmarketing in temporal association
with the use of PDE5 inhibitors, including vardenafil. Most, but not all, of
these patients had underlying anatomic or vascular risk factors for development
of NAION, including but not necessarily limited to: low cup to disc ratio
(“crowded disc”), age over 50, diabetes, hypertension, coronary artery disease,
hyperlipidemia and smoking. It is not possible to determine whether these
events are related directly to the use of PDE5 inhibitors, to the patient's
underlying vascular risk factors or anatomical defects, to a combination of
these factors, or to other factors [see WARNINGS AND PRECAUTIONS and PATIENT INFORMATION].

Visual disturbances including vision
loss (temporary or permanent), such as visual field defect, retinal vein
occlusion, and reduced visual acuity, have also been reported rarely in
postmarketing experience. It is not possible to determine whether these events
are related directly to the use of vardenafil.

Otologic: Cases of sudden decrease
or loss of hearing have been reported postmarketing in temporal association
with the use of PDE5 inhibitors, including vardenafil. In some cases, medical
conditions and other factors were reported that may have also played a role in
the otologic adverse events. In many cases, medical follow-up information was
limited. It is not possible to determine whether these reported events are
related directly to the use of vardenafil, to the patient's underlying risk
factors for hearing loss, a combination of these factors, or to other factors [see
PATIENT INFORMATION].

DRUG INTERACTIONS

The drug interaction studies described below were
conducted using vardenafil film-coated tablets.

Potential For Pharmacodynamic Interactions With STAXYN

Nitrates: Concomitant use of STAXYN and nitrates
is contraindicated. The blood pressure lowering effects of sublingual nitrates
(0.4 mg) taken 1 and 4 hours after vardenafil and increases in heart rate when
taken at 1, 4 and 8 hours after vardenafil were potentiated by a 20 mg dose of
vardenafil in healthy middle-aged subjects. These effects were not observed
when vardenafil 20 mg was taken 24 hours before the nitroglycerin (NTG).
Potentiation of the hypotensive effects of nitrates for patients with ischemic
heart disease has not been evaluated, and concomitant use of STAXYN and
nitrates is contraindicated [see CONTRAINDICATIONS and CLINICAL
PHARMACOLOGY].

Alpha-Blockers: Patients taking alpha-blockers
should not initiate vardenafil therapy with STAXYN. Patients treated with
alpha-blockers who have previously used vardenafil film-coated tablets may be
switched to STAXYN at the advice of their healthcare provider. Caution is
advised when PDE5 inhibitors are co-administered with alpha-blockers. PDE5
inhibitors, including STAXYN and alpha-adrenergic blocking agents are both
vasodilators with blood-pressure-lowering effects. When vasodilators are used
in combination, an additive effect on blood pressure may be anticipated. Clinical
pharmacology studies have been conducted with co-administration of vardenafil
with alfuzosin, terazosin or tamsulosin. [See DOSAGE AND ADMINISTRATION,
WARNINGS AND PRECAUTIONS, and CLINICAL PHARMACOLOGY]

Antihypertensives: STAXYN may add to the blood
pressure lowering effect of antihypertensive agents. In a clinical pharmacology
study of patients with erectile dysfunction, single doses of 20 mg vardenafil
caused a mean maximum decrease in supine blood pressure of 7 mmHg systolic and
8 mmHg diastolic (compared to placebo), accompanied by a mean maximum increase
of heart rate of 4 beats per minute. The maximum decrease in blood pressure
occurred between 1 and 4 hours after dosing. Following multiple dosing for 31
days, similar blood pressure responses were observed on Day 31 as on Day 1.

Alcohol: Vardenafil 20 mg did not potentiate the
hypotensive effects of alcohol during the 4-hour observation period in healthy
volunteers when administered with alcohol (0.5 g/kg body weight: approximately
40 mL of absolute alcohol in a 70 kg person). Alcohol and vardenafil plasma
levels were not altered when dosed simultaneously.

Effect Of Other Drugs On Vardenafil

In vitro studies

Studies in human liver microsomes showed that vardenafil
is metabolized primarily by cytochrome P450 (CYP) isoforms 3A4/5, and to a
lesser degree by CYP2C9. Therefore, inhibitors of these enzymes are expected to
reduce vardenafil clearance [see DOSAGE AND ADMINISTRATION and WARNINGS
AND PRECAUTIONS].

In vivo studies

Do not use STAXYN with moderate and potent CYP3A4
inhibitors such as erythromycin, grapefruit juice, clarithromycin,
ketoconazole, itraconazole, indinavir, saquinavir, atazanavir, ritonavir as the
systemic concentration of vardenafil is increased in their presence [see WARNINGS
AND PRECAUTIONS and DOSAGE AND ADMINISTRATION].

Potent CYP3A4 inhibitors

Ketoconazole (200 mg once daily) produced a 10-fold
increase in vardenafil area under the curve (AUC) and a 4-fold increase in
maximum concentration (C max ) when co-administered with vardenafil 5 mg in
healthy volunteers. [See DOSAGE AND ADMINISTRATION and WARNINGS AND
PRECAUTIONS]

Indinavir (800 mg t.i.d.) co-administered with vardenafil
10 mg resulted in a 16-fold increase in vardenafil AUC, a 7-fold increase in
vardenafil Cmax and a 2-fold increase in vardenafil half-life. [See DOSAGE
AND ADMINISTRATION and WARNINGS AND PRECAUTIONS]

Ritonavir (600 mg b.i.d.) co-administered with vardenafil
5 mg resulted in a 49-fold increase in vardenafil AUC and a 13fold increase in
vardenafil C max . The interaction is a consequence of blocking hepatic
metabolism of vardenafil by ritonavir, a HIV protease inhibitor and a highly
potent CYP3A4 inhibitor, which also inhibits CYP2C9. [See DOSAGE AND
ADMINISTRATION and WARNINGS AND PRECAUTIONS]

Moderate CYP3A4 inhibitors

Erythromycin (500 mg t.i.d.) produced a 4-fold increase
in vardenafil AUC and a 3-fold increase in vardenafil C max when
co-administered with vardenafil 5 mg in healthy volunteers [see DOSAGE AND
ADMINISTRATION and WARNINGS AND PRECAUTIONS].

Other Drug Interactions

No pharmacokinetic interactions were observed between
vardenafil and the following drugs: glyburide, warfarin, digoxin, an antacid
based on magnesium-aluminum hydroxide, and ranitidine. In the warfarin study,
vardenafil had no effect on the prothrombin time or other pharmacodynamic
parameters.

Cimetidine (400 mg b.i.d.) had no effect on AUC and C max
of vardenafil when co-administered with 20 mg vardenafil in healthy volunteers.

Effects Of Vardenafil On Other Drugs

In vitro studies

Vardenafil and its metabolites had no effect on CYP1A2,
2A6, and 2E1 (Ki > 100 micromolar). Weak inhibitory effects toward other
isoforms (CYP2C8, 2C9, 2C19, 2D6, 3A4) were found, but Ki values were in excess
of plasma concentrations achieved following dosing. The most potent inhibitory
activity was observed for vardenafil metabolite M1, which had a Ki of 1.4
micromolar toward CYP3A4, which is about 20 times higher than the M1 C max values
after an 80 mg vardenafil dose.

In vivo studies

Nifedipine: Vardenafil 20 mg, when co-administered
with slow-release nifedipine 30 mg or 60 mg once daily, did not affect the
relative AUC or C max of nifedipine, a drug that is metabolized via CYP3A4.
Nifedipine did not alter the plasma levels of vardenafil when taken in
combination. In these patients whose hypertension was controlled with
nifedipine, vardenafil 20 mg produced mean additional supine systolic/diastolic
blood pressure reductions of 6/5 mmHg compared to placebo.

Ritonavir and Indinavir: Upon concomitant
administration of 5 mg vardenafil with 600 mg b.i.d. ritonavir, the C max and
AUC of ritonavir were reduced by approximately 20%. Upon administration of 10
mg of vardenafil (film-coated tablets) with 800 mg t.i.d. indinavir, the Cmax and
AUC of indinavir were reduced by 40% and 30%, respectively.

Aspirin: Vardenafil 10 mg and 20 mg did not
potentiate the increase in bleeding time caused by aspirin (two 81 mg tablets).

Other Interactions: Vardenafil had no effect on
the pharmacodynamics of glyburide (glucose and insulin concentrations) and
warfarin (prothrombin time or other pharmacodynamic parameters).

Last reviewed on RxList: 5/19/2014
This monograph has been modified to include the generic and brand name in many instances.